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Issues in Risk Assessment The committee began meeting in January 1990 and selected as its first topic of study and use of the maximum tolerated dose (MTD) in animal bioassays, with emphasis on the relationship between the MTD and the carcinogenic potency of a test chemical. The second topic was the two-stage model of carcinogenesis, with a focus on data requirements for regulatory application. The third topic was a conceptual framework for ecologic risk assessment. The committee's reports on those three subjects make up this volume. Two other topics that have been selected are exposure assessment and developmental toxicity; workshops on these topics have been held, and reports are in preparation. Use of the Maximum Tolerated Dose in Animal Bioassays for Carcinogenicity Long-term animal bioassays for carcinogenicity are used regularly to determine whether chemical agents are capable of inducing cancer in exposed animals. Two important aspects of current bioassays are that testing covers a substantial portion of the lifespan of the test species and that high doses are used. The highest dose tested (HDT) is an approximation of the maximum tolerated dose (MTD), which is roughly described as the highest dose that does not alter the test animal's longevity or well-being because of noncancer effects. The committee chose as its first task to address the use and limitations of MTD testing in long-term animal bioassays for carcinogenicity. The first report focuses specifically on whether the MTD should continue to be used in carcinogenicity bioassays, and it does not address all the issues related to performing carcinogenicity bioassay or interpreting their results. In particular, the committee chose to investigate the observation that statistical analyses of the results of bioassays of many chemicals have shown strong correlations between measures of carcinogenic potency, such as the TD50 (the dose that causes tumors in 50% of test animals that would otherwise be tumor-free), and measures of toxicity, including the MTD. The strength of the correlations suggests that carcinogenicity is inherently related in some way to other toxic effects produced by a chemical, although dependence on such factors as the bioassay design and the mathematical and statistical methods used to estimate potency and investigate the correlations has also been proposed.
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Issues in Risk Assessment The committee concluded that the correlations are not wholly mathematical or statistical artifacts, but are due partially to an underlying relationship between measures of general toxicity (e.g., the MTD) and measures of carcinogenic potency. The relationship can be expressed as follows: increases in cancer incidence large enough to be detected (i.e., to be statistically significant) in standard bioassays generally occur only at doses near the MTD. The committee suggests that because of the relationship between TD50s and the MTDs, a preliminary (and perhaps uncertain) estimate of the potential carcinogenic potency of an untested chemical can be derived from its MTD. Such an estimate is a plausible upper bound on the carcinogenic potency of a chemical, if in fact it is a carcinogen. Such estimates can prove useful in setting priorities for carcinogenicity testing and in estimating cancer risk when carcinogenicity data are not available. If an upper-bound estimate predicts a small human risk, a chemical could be given a low priority for carcinogenicity testing or might be deemed suitable for use with less extensive testing than might otherwise be required. The committee noted that because specific criteria for selecting the HDT vary, even under the current guidelines, reports of bioassay results should include a clearly stated rationale for dose selection and a summary of the toxicity information important for evaluating the dose selection to facilitate interpretation. The usefulness of information from bioassays conducted at the MTD has been questioned for several reasons. First, some believe that the proportion of compounds found to be carcinogenic at the MTD is so large that regulatory attention and public concern might be applies to agents that pose only trivial hazards. (The committee did not review such regulatory attention.) Second, it has been argued that some agents induce cancer at the MTD through mechanisms that do not occur at lower doses. Several mechanisms of carcinogenesis have been hypothesized to be effective only at high doses, such as increased cell proliferation rates in response to high dose toxicity or as a result of receptor complex-mediated alterations in cell growth control. According to these hypotheses, exposure at lower doses, where these mechanisms are inactive, would not result in a carcinogenic response. (The committee noted several examples of agents for which these hypotheses had been proposed, but did not reach conclusions on their proof or consensus on the generality of their application.) Third, it has been asserted that current
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Issues in Risk Assessment bioassays, which generally involve only doses at or near the MTD, provide little information that is useful for defining the dose-response relationship. Defining the shape of the dose-response curve at lower doses would provide information that has greater relevance to human exposures and consequent risks. (The committee noted that validation of methods for extrapolation of dose-response relationship over wide ranges was beyond the scope of the study, although human exposure to some carcinogens at doses approximating those used in bioassays is known to occur.) The committee noted several limitations in the information provided by current bioassays that use the MTD. Those assays often do not incorporate doses smaller than one-fourth of the MTD, so they do not provide direct information on the carcinogenic potential of a test substance at lower doses. But tests conducted at lower doses will probably have little power to detect carcinogenic effects, unless the number of animals tested is increased immensely, which would increase the cost of a bioassay commensurately; the large number of animals required for detection of the smaller increase in tumors incidence that might occur at low doses is one of the primary reasons for use of the MTD in carcinogenicity bioassays. Testing at doses that induce overt toxicity, however, can lead to changes in an animal's food consumption, recurrent cytotoxicity, and hormonal imbalance, all of which an increase or decrease carcinogenic responses at particular target sites. A rodent bioassay might yield information whether a chemical produces tumors in rodents, but generally can provide only scanty information on whether it produces tumors through generalized indirect mechanisms or directly as a result of its specific properties. Other data are required for extrapolating bioassay results to other doses or from animals to humans or for evaluating the possibility that indirect mechanisms of carcinogenesis can contribute to the results. Despite those limitations, the majority of the committee concluded that current bioassays that incorporate the MTD provide some information that is useful for hazard identification and risk assessment. The assays identify substances that do or do not increase the incidence of cancer under standardized test conditions; in the case of substances that do not increase the incidence, the assays provide an operational definition of noncarcinogen. They identify target organs that show which tumor types are associated with exposure, thereby providing guidance
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Issues in Risk Assessment for epidemiologic studies, although concordance among species is often absent. They also provide a basis for interspecies comparisons and they provide useful information on the carcinogenic potency of a chemical at high doses, as well as on differences in sensitivity between the sexes and among different strains and species of rodents, which are the test animals almost universally used. The committee recognizes that bioassays conducted at the MTD are not designed to provide information on a biochemical and physiologic mechanisms of tumors production. Nor do they provide direct information on the shape of the dose-response curve at doses below the lowest experimental dose, which often include doses to which humans are exposed. The committee considered four major options for modification of current bioassay procedures: (1) retain the status quo, possibly with the addition of doses lower than the MTD; (2) use a high dose that is an arbitrary fraction of the estimated maximum tolerated dose; (3) redefine the MTD, basing it on studies of the dose dependence of physiologic effects expected to alter carcinogenic response; and (4) use MTD testing as part of an overall testing strategy that separates carcinogens from noncarcinogens but also provides additional information useful for determining human relevance. After extensive deliberation and consideration of those options, the committee was unable to come to a unanimous decision on a recommendation. Two points of view emerged. The majority of the committee considered option 4 (which recommends that the MTD, as currently defined, continue to be one of the doses used in carcinogenicity bioassays) to be appropriate and prudent. However, a sizable minority (six of the 17 committee members) did not fully agree with the conclusions and recommendations reached by the majority and prepared an alternative recommendation. The two groups' recommendations are summarized below. The majority of the committee prefers option 4 and recommends that the MTD, as currently defined, continue to be one of the doses used in carcinogenicity bioassays. Other doses, from one-half to possibly one-tenth of the MTD or even smaller, should also be used, taking into account the capacity of the test animals to metabolize the test substance. If bioassay results are negative in both sexes of two species, generally no additional tests related to carcinogenicity are required. If the results
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Issues in Risk Assessment are positive, additional studies should be performed to reduce uncertainties in the prediction of human responses to the material and in the quantification of human risk. The additional studies should address mechanisms of cancer induction, toxicokinetics and metabolism of the substance, and physiologic responses induced by the substance. The committee notes that regulation of a chemical can be instituted (for public health reasons and to protect human lives while more data are being collected) at almost any stage of data collection and that regulation can be modified as additional data become available. The minority of the committee believes that the process for selecting doses to be used in a carcinogenicity bioassay should be modified (option 3). Specifically, the minority recommends that dose selection be done by a panel of experts on the basis of careful evaluation of appropriate subchronic studies conducted before the bioassay is initiated. The HDT should be chosen as the highest dose that can be expected to yield results relevant to humans, not simply the highest dose that can be administered to animals without causing early mortality from causes other than cancer (i.e., the MTD as currently defined). (In contrast, the majority believes that the decision regarding results obtained with the MTD can best be made after the MTD data are collected and that future decisions—regarding either regulation or additional studies—are better grounded if these data are present than if they are absent. The minority recognizes that chronic animal bioassays were originally designed to answer a simple question: Can chemicals cause cancer in animals? It is clear that the primary motivation for conducting the chronic bioassay today, however, is to determine whether the substances tested are likely to pose a substantial cancer risk to human populations. Therefore, the minority finds that a core of basic information should be gathered before the chronic bioassay is initiated, so that the study can be designed to achieve its objective. The minority therefore recommends that the HDT in a bioassay be selected after a careful evaluation of results of subchronic studies conducted before the 2 year bioassay (option 3). In option 3, a core of basic information gathered before the bioassay would include information about the mechanisms of toxicity in test animals and an elucidation of the dose-response curve for such toxicity. That information is important because there is concern that induction of substantial toxicity throughout the lifetime of an animal might affect the rate at which tu-
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Issues in Risk Assessment mors develop. Information would also be required on how dosage (including repeated exposures) affects biochemical and physiologic processes that are responsible for homeostasis, cell proliferation, hormonal balance, and the uptake and metabolism of the test chemical. All those processes are known to influence cancer incidence. In some circumstances, adoption of option 3 would not change the magnitude of the HDT. For example, if human populations were exposed to high concentrations of the test substance, the HDT might be the MTD. However, in many cases, the HDT could be much lower than the current MDT, and the range of doses tested might be much wider than that used in current studies. The principles recommended by Sontag et al. in 1976 (and endorsed by the majority of the committee) were designed to minimize the frequency of false-negative results (i.e., to maximize the sensitivity of the bioassay). The minority believes that the changes it recommends would improve the relevance of the bioassay for human populations by increasing the specificity of the test. (The majority points out that any increase in specificity resulting from the change proposed by the minority would be accompanied by a decrease in sensitivity, and the committee did not investigate the extent to which the change would allow human carcinogenicity to go undetected.) The minority recognizes the implementation of option 3 would not be trivial. Guidelines for the amount of information required before bioassays are initiated would have to be modified. Criteria for dose selection would vary from chemical to chemical. It is clearly beyond the scope of the minority recommendation to specify all the details for this paradigm shift. However, the minority believes that implementation of its recommendation is feasible within the current testing framework. For example, review of scientific criteria for selection of bioassay doses by the National Toxicology Program (NTP) could be carried out by its Board on Scientific Counselors. (The board currently reviews the selection of compounds to be tested by NTP and reviews NTP's reports, but does not review the selection of doses for testing by NTP.) Other testing organizations might use other review boards before commencing studies. The inability of the committee to come to unanimity on its primary recommendations reflects differing judgments on which approach to